1. Field of the Invention
The present invention relates generally to immunomodulation and, more specifically, to therapeutic uses of immunostimulatory Proteosome compositions for inducing a nonspecific immune response (such as an innate immune response) so that an adaptive immune response is potentiated or enhanced, or to induce both a nonspecific immune response and a specific adaptive immune response, such that infectious disease is treated or prevented, or to modulate an immune response for treating or preventing an inflammatory reaction, such as allergic asthma.
2. Description of the Related Art
Some microbial pathogens are capable of causing fatal infections even when faced with a robust host immune response. Nonetheless, control of rampant infectious disease has been generally successful in modern society by using strict public health measures, drugs (such as antibiotics) and vaccines. Vaccines typically include an attenuated microbe or a microbial antigen to activate a specific (adaptive) immune response. The ability of an antigen to induce a protective immune response in a host can be enhanced by formulating the antigen with an immunostimulant or an adjuvant. Alum-based adjuvants are almost exclusively used for licensed, injectable human vaccines. However, the adaptive immune response requires signals that provide information about the origin of the antigen (i.e., self versus non-self antigens) and the type of response to be induced (i.e., a T cell and/or B cell response). Evidence recently accumulated indicates that these signals may be provided by the innate immune system (see, e.g., Fearon and Locksley, Science 272:50, 1996; Medzhitov and Janeway, Curr. Opin. Immunol. 9:4, 1997).
Innate immunity is the first line of antibody-independent defense against infections and, in many instances, can eliminate infectious agents. The components of innate immunity recognize structures that are characteristic of microbial pathogens and are not present on mammalian cells. The principle effector cells of innate immunity are neutrophils, mononuclear phagocytes, and natural killer (NK) cells. Neutrophils and macrophages express surface receptors that recognize microbes in the blood and tissues, and either stimulate the ingestion (phagocytosis, e.g., mannose or opsonin receptors) or activate phagocytes not involved in ingestion (e.g., Toll-like receptors, TLRs). The effector mechanisms of innate immunity are often used to eliminate microbes, even in an adaptive immune response. Thus, the innate immune response can provide signals that function in concert with antigen to stimulate the proliferation and differentiation of antigen-specific (adaptive) T and B lymphocytes.
An efficient immune response depends on the communication between the innate and adaptive immune responses. The T lymphocyte is important for coordinating the adaptive immune response by controlling the release of effector molecules. For example, T helper (Th) 1 cells produce interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ), which are important for the development of cell-mediated immunity (Mosmann et al., J. Immunol. 136: 2348, 1986; Street and Mosmann, FASEB J. 5: 171, 1991). In contrast, Th2 cells produce IL-4, IL-13, IL-5, IL-9, IL-6 and IL-10, which are important for the stimulation of IgE production, mucosal mastocytosis, and eosinophilia (Mosmann et al.; Street and Mosmann). While a shift toward a Th1 or Th2 phenotype may be important for the defense against pathogens, a shift in one direction or another can also be associated with the induction of autoimmune disease (Th1) or inflammatory disease (Th2).
In inflammatory diseases, such as allergy or asthma, the fine balance between the Th1, Th2 and T regulatory cytokine responses appears to shift toward a Th2 phenotype. For example, asthma is a complex inflammatory disease of the lung characterized by variable airflow obstruction, airway hyperresponsiveness (AHR), and airway inflammation. Although asthma is multifactorial in origin, the inflammatory process (in the most common form of asthma, referred to as extrinsic or allergic asthma) is believed to be the result of an abnormal immune response to commonly inhaled allergens. The presentation of inhaled allergens to CD4+ T cells in the lungs of susceptible individuals results in the production of Th2 cytokines, IL-4, IL-13 and IL-5, which control the differentiation, recruitment, and activation of mast cells and eosinophils in the airway mucosa. These effector cells release a variety of inflammatory mediators (e.g., histamine, mucous secretogues, eosinophil-derived basic proteins, proteases). The mediators either individually or in concert cause acute bronchoconstriction, disruption of the airway epithelial layer, alterations in neural control of airway tone, increased mucus production, and increased smooth muscle cell mass. Each of these consequences of the inflammatory process may cause or occur in combination with AHR. The incidence, morbidity, and mortality of asthma has increased worldwide over the last two decades, and the existing anti-inflammatory medications (such as corticosteroids) have limitations in that the disease is not modified (i.e., only the symptoms are treated, which will return if the medication is discontinued) and these medications are associated with the potential for significant side effects.
Hence, a need exists for identifying and developing immunostimulatory compositions that are therapeutically effective against microbial infections and immunopathologic (e.g., inflammatory) responses to such infections, particularly compositions that can potentiate or enhance protective immunity, and compositions that can suppress an immunopathologic response. The present invention meets such needs, and further provides other related advantages.